1. Field of the Invention
The present invention relates to new cephalosporin intermediates, particularly to new 7-.beta.-glutarylamido cephalosporins and to processes for obtaining them, useful for the preparation of therapeutically, important cephalosporinic antibiotics.
2. Description of the Background
It is well known that the major part of semisynthetic cephalosporins is obtained from 7-aminocephalosporanic acid (7-ACA) by acylation reactions of the amino group in 7 and by nucleophilic substitution of the acetoxy group in 3'. 7-ACA is still industrially produced by chemical hydrolysis of cephalosporin C through a complicated process which involves reagents and solvents very toxic and polluting and extreme working conditions.
Enzymatic or chemical-enzymatic processes by glutaryl 7-ACA have been lately developed to overcome these shortcomings. Said processes provide two steps, in the first step cephalosporin C is transformed enzymatically in an aqueous medium in glutaryl 7-ACA, by oxidative deamination with D-aminoacid oxidase [(BE-A-736934 (Glaxo); JP-A-40588 (Asahi); EP-A-0496993 (Antibioticos)], or chemically, by oxidative transamination [U.S. Pat. No. 4,079,180 (Asahi)]. The glutaryl 7-ACA is then deacylated by the glutaryl 7-ACA acylase enzyme [JP-A-186599 (Asahi); EP-A-0496993 (Antibioticos)].
7-ACA cannot be used per se for the syntheses of the latest cephalosporins, for instance the 3-alkenyl- ones (Cefprozil, Cefdinir), and the quaternary 3'-ammoniummethyl ones (Cefepime), but it has to be first undergone to protection reactions of the amino group (for instance by acylation or transforming it in a Schiff's base) and of the carboxy group (for instance by esterification). Besides, using 7-ACA is expensive for preparing specific cephalosporins such as the 3-cephem-3-halo substituted (for instance Cefaclor) or the unsubstituted ones (norcephalosporins, for instance Ceftizoxime and Ceftibuten), and the industrial processes known hitherto for the production thereof use, as starting materials, compounds containing the penicillinic core, for instance penicillin G or V, and come to obtaining the desired final products by a complicated sequence of chemical reactions which may provide, subsequently, protecting of carboxyl, sulfoxidation, the opening of the penicillanic ring, the rearrangement to cephalosporanic ring, etcetera. See, at this purpose, U.S. Pat. Nos. 4,052,387, 4,075,203, 4,081,440, 415,372, 4,031,084 and 4,346,218.
It is apparent that the glutaryl 7-ACA is not only cheaper than 7-ACA but it shows a variety of advantages, from a chemical-synthetic point of view, in respect with 7-ACA and cephalosporin C itself, the latter being sometimes used to produce cephalosporinic antibiotics. Yet, isolating glutaryl 7-ACA , given its high water solubility, is technically hard and expensive.
Other 7-ACA derivatives such as the known halomethyl derivatives, for instance the 3-chloromethyl or 3-bromomethyl derivatives, are obtained from 7-ACA by a complicated sequence of protection reactions of the amino and carboxy groups, or by esters--sulfoxides of penicillin G by sophisticated technologies (opening of the penicillinic ring, electrochemical chlorinating, rearrangement to cephalosporinic ring).
Also the 3-exomethylene--derivatives of 7-ACA have a key structure for obtaining important cephalosporinic antibiotics. A few methods are known for transforming cephem derivatives into 3-exomethylene cepham derivatives.